Lithium is one of the oldest psychiatric drugs in existence. Lithium salt compositions, including lithium carbonate (Li2CO3) lithium citrate (Li3C6H5O7), are commonly used lithium compounds prescribed for treatment. Lithium is commonly used to treat bipolar disorder and acute mania, mania (DSM-II and DSM-III). Lithium is also used for other disorders, such as depression, schizophrenia, epilepsy, for eating disorders, including anorexia and bulimia, cyclical vomiting, and alcoholism. It has also been used for anemia and neutropenia, liver disease, kidney disorders, thyroid adjustment, Huntington's disease, Grave's disease, Tourette's syndrome, and in some cases of attention deficit-hyperactivity disorder.
Alternative lithium salts that have been proposed for use include lithium orotate (C5H3LiN2O4), lithium bromide (LiBr) and lithium chloride (LiCl). However, it was found that lithium bromide and lithium chloride are toxic. Further, other salts, such as lithium fluoride (LiF) and lithium iodide (LiI), are assumed to toxic and have not been tested. This is further complicated by the fact that lithium compounds have a small therapeutic window, with the U.S. National Library of Medicine providing a therapeutic range of 0.8 to 1.2 mEq/L. On administration, lithium generally reaches peak plasma levels at 30 minutes to 2 hours, though peak plasma levels after overdoses can take 72 hours (Timmer & Sands, Lithium intoxication. J Am Soc Nephrol. 1999 Mar. 1; 10(3):666-74). CNS levels of lithium are approximately 40% of plasma levels due to active transport of lithium out of the CNS, and levels peak about 24 hours after plasma levels peak (Timmer & Sands, Lithium intoxication. J Am Soc Nephrol. 1999 Mar. 1; 10(3):666-74). The drug elimination half-life is 24 hours for acute treatment, and can vary to 60 hours for some chronically treatment individuals (Timmer & Sands, Lithium intoxication. J Am Soc Nephrol. 1999 Mar. 1; 10(3):666-74). Typically serum levels greater than 1.5 mEq/l increase the likelihood of toxicity and detrimental effects while levels of 2.0 or higher are considered toxic (U.S. National Library of Medicine).
Lithium toxicity can present as drowsiness, course muscle tremors or weakness, nausea, seizures, problems with muscle control, such as speaking, eye control, or locomotor control, vomiting, diarrhea, coma and death. Toxicity also affects cerebral function, and can cause neuropathy, as well as heart abnormalities.
Therapeutic levels of lithium interact with various neurotransmitters and receptors, causing decreases in norepinephrine (noradrenaline) release and increasing serotonin synthesis. In vitro, rat serotonergic neuron cultures treated with lithium resulted in serotonin release during a depolarization compared to no lithium treatment and the same depolarization. Other studies have shown lithium may interact with nitric oxide (NO) signaling in the central nervous system, which plays a crucial role in the neural plasticity, and lithium inhibits inositol monophosphatase that results in higher inositol triphosphate. Due to the pharmacological effects of lithium, as well as its bioactivity, the drug remains heavily utilized by clinicians today despite intense marketing of newer alternative drugs that do not contain the toxicity issues that require frequent blood monitoring by a clinician.
Long-term lithium therapy has been linked to altered kidney functioning, resulting in reduced capacity of renal concentrating ability, and occasionally nephrogenic diabetes insipidus, with polyuria and polydipsia. Some studies have linked reduction in kidney functioning to morphological changes in the nephrons.
Recently, there have been efforts to find a “lithium mimetic” with improved safety (Singh, et al., A safe lithium mimetic for bipolar disorder. Nat Commun. 2013 Jan. 8; 4:1332; Gould & Manji, Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology. 2005 July; 30(7):1223-37). For example, such as ebselen which inhibits inostilol monophosphatase to produce a lithium-like response in mouse models (Singh, et al., A safe lithium mimetic for bipolar disorder. Nat Commun. 2013 Jan. 8; 4:1332). Alternatively, others have used crystal engineering techniques to re-engineer lithium therapeutics by creating novel ionic cocrystals of lithium salts (Smith et al., Reinventing lithium therapeutics by crystal engineering of novel ionic cocrystals. Mol Pharm. 2013 Dec. 2; 10(12):4728-38; Braga et al., Combining piracetam and lithium salts: ionic co-crystals and co-drugs? Chem Commun (Camb). 2012 Aug. 25; 48(66):8219-21; Wouters, et al., Novel Pharmaceutical Compositions through Co-crystallization of Racetams and Li+ Salts. Cryst Eng Comm. 2013 Aug. 2, 15:8898-8902). Cocrystallization represents a low risk, low cost approach with the most potential for achieving the desired therapeutic outcome for many reasons. For example, the active pharmaceutical ingredient (API) in this crystal engineering approach remains lithium, which is already FDA approved with a long history of use in medicine. Furthermore, the FDA has just released draft guidance for industry regarding the regulation of pharmaceutical cocrystals that includes an expedited pathway for their approval (FDA. April 2013. Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals. In Services UDoHaH, Administration FaD, Research CfDEa, editors., ed.). Thus, the cost to bring a lithium cocrystal drugs to market will likely be significantly lower than that of a new drug. However, none of these chemical entities have matched lithium's polypharmacological mechanisms of action for the treatment of neuropsychiatric diseases. Because lithium is so effective at treating neuropsychiatric diseases such as bipolar disorder and suicidality (Baldessarini, et al., Treating the suicidal patient with bipolar disorder. Reducing suicide risk with lithium. Ann N Y Acad Sci. 2001 April; 932:24-38; Goodwin, et al., Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003 Sep. 17; 290(11):1467-73; Thies-Flechtner, et al., Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Data from a randomized prospective trial. Pharmacopsychiatry. 1996 May; 29(3):103-7) it is still considered the gold standard for treatment of mania, despite known toxicity issues that require frequent blood monitoring by a clinician.
Consequently there exists a need to re-engineer lithium therapeutics, such as through use of cocrystallization, to improve pharmacokinetics, and optimizing safety and efficacy. Accordingly, what is needed is a method for treating a neurological disorder using a novel ionic cocrystals of lithium salts where the anion of the lithium salt is pharmaceutically acceptable and contains appropriate blood and brain pharmacokinetics.